title: Increased systemic cortisol metabolism in patients with schizophrenia and bipolar disorder: a mechanism for increased stress vulnerability?
abstract: OBJECTIVE
  The hypothalamic-pituitary-adrenal (HPA) axis seems dysregulated and part of the pathophysiology in bipolar disorder and schizophrenia, but the underlying mechanisms are unknown. Recent evidence indicates that systemic cortisol metabolism influences blood cortisol levels and HPA axis functioning. Our objective was to estimate systemic cortisol metabolism by means of the activity of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenase (11β-HSD) in patients with bipolar disorder and schizophrenia spectrum disorders compared to healthy controls.
  
  
  METHODS
  Inpatients and outpatients aged 18 to 65 years with DSM-IV bipolar disorder (n = 69) or schizophrenia (n = 87) were consecutively recruited to the catchment area-based Thematically Organized Psychosis Research (TOP) study. Healthy controls (n = 169) were randomly selected from statistical records from the same catchment area and were contacted by letter inviting them to participate. Spot urine samples were collected in a cross-sectional manner from November 2006 to November 2008. Urinary free cortisol and cortisone and their metabolites were analyzed with liquid chromatography tandem mass spectrometry and used as indicators of 5α-reductase, 5β-reductase, and 11β-HSD activity.
  
  
  RESULTS
  The combined patient group had increased activity of 5α-reductase, 5β-reductase, and 11β-HSD2 (all P < .001) compared to controls. Elevated systemic cortisol metabolism was present in both schizophrenia (5α-reductase, 5β-reductase, and 11β-HSD2; all P < .001) and bipolar disorder (5α-reductase [P = .016], 5β-reductase [P = .001], and 11β-HSD2 [P = .007]).
  
  
  CONCLUSIONS
  The results indicate increased activity of cortisol metabolism in patients with bipolar disorder and schizophrenia compared to healthy controls and suggest that increased systemic cortisol metabolism is involved in the pathophysiology and stress vulnerability in these severe mental disorders. The findings should be explored further in terms of potential new drug targets, and they add to the physiologic rationale for stress coping strategies in these patient groups.
authors.affiliation: Section for Psychosis Research, Clinic of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. n.e.steen@medisin.uio.no
authors.forename: Nils Eiel
authors.initials: NE
authors.lastname: Steen
authors.forename: Paal
authors.initials: P
authors.lastname: Methlie
authors.forename: Steinar
authors.initials: S
authors.lastname: Lorentzen
authors.forename: Sigrun
authors.initials: S
authors.lastname: Hope
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Barrett
authors.forename: Sara
authors.initials: S
authors.lastname: Larsson
authors.forename: Erlend
authors.initials: E
authors.lastname: Mork
authors.forename: Bjørg
authors.initials: B
authors.lastname: Almås
authors.forename: Kristian
authors.initials: K
authors.lastname: Løvås
authors.forename: Ingrid
authors.initials: I
authors.lastname: Agartz
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.forename: Jens P
authors.initials: JP
authors.lastname: Berg
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000201:enzymology / Q000378:metabolism*; D003348:Cortisone / Q000378:metabolism* / Q000652:urine; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000378:metabolism*; D012559:Schizophrenia / Q000201:enzymology / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D010088:Oxidoreductases; D003348:Cortisone; D006854:Hydrocortisone